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Transcript of Corifollitropin alpha Elonva P Devroey. GnRH antagonist Reduced patients’ burden and psychological...
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Corifollitropin alphaElonva
P Devroey
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GnRH antagonist
Reduced patients’ burden and psychological stress
Patient friendly
Short duration
Similar pregnancy outcome Meta – analysis
Reduced risk of OHSS correlated with GnRH long protocols
Strategy to erase OHSS with GnRH agonist trigger
Safe
OHSS risk Zero
Devroey HR 2009
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Meta-analysis of efficacy trials:probability of live birth
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Oral Contraceptive Pretreatment Significantly Reduces Ongoing Pregnancy Likelihood in GnRH Antagonist Cycles: A Meta-Analysis
Griesinger et al Fertil Steril 2010
The probability of an ongoing pregnancy per randomized woman was found to be significantly lower in patients who received oral contraceptive pill pre-treatment (RR 0.80, 95% CI: 0.66 to 0.97; p=0.02
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Oral contraceptive pretreatment
Study OCP (n) No OCP (n)
Total 670 673
Risk Ratio 0.80 (0.66, 0.97)
In favour of no OCP 1 pregnancy loss/ 20 women treated
Meta-analysis
Griesinger FS 2010
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Oral contraceptive pills in GnRH antagonist protocol versus long protocol
OCP + GnRH antagonist ( n) (%)
Long Protocol (n) (%)
Ongoing PR 55/115 (48) 61/113 (54)
Multiples 15/55 (27) 18/61 (30)
Implantation Rate 75/207 (36) 80/204 (39)
Live birth rate 51/115 (44) 53/113 (47)
Garcia-Velasquo FS 2011
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Randomization
Patients received 10.000 IU of hCG
as soon as ≥ 3 follicles of ≥ 17 mm were present in ultrasound
early hCG group, 208 patients
or
2 days later after this criterion was met
late hCG group, 205 patients
Kolibianakis Albano Camus Tournaye Van Steirteghem Devroey FS 2004
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Prolongation of the follicular phase in IVF results in a lower probability of pregnancy
Early-hCG group Late-hCG group P
Ongoing pregnancy rate per OPU (n)
35.6%
(69/194)
25%
(49/196)
0.027
Ongoing pregnancy rate per ET (n)
39.2%
(69/176)
27.7%
(49/177)
0.024
Ongoing implantation rate (n)
22.6%
(87/385)
15.1%
(58/383)
0.009
Kolibianakis FS 2004
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How to manage patients with elevated progesterone levels at initiation of stimulation ?
Patients with elevated progesterone levels on day two of the cycle were always postponed for 1-2 days
Stimulation with rec-FSH and GnRH antagonists was started only if progesterone levels returned to normal range
Kolibianakis et al HR 2004
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Elevated progesterone levels at initiation of
stimulation are associated with a significantly lower
chance of pregnancy
Normal P group High P group
P Difference (95% CI)
Ongoing pregnancy rate
Per started cycle % (n)
31.8 (124/390) 5.0 (1/20) 0.011 26.8 (7.7-33.1)
Per oocyte retrieval % (n)
33.8 (124/367) 6.3 (1/16) 0.026 27.5 (5.0-34.7)
Further research Initiation of antagonist on day 1?
Kolibianakis HR 2004
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Describe the LH concentration during the luteal phase ( post hCG ) in agonist gonadotrophin stimulated cycles
LOW or HIGH
Answer : Low
Smitz HR 1988
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Answer : decreased
Is the luteal phase LH concentration ( post hCG ) in antagonist - gonadotrophin cycles
normal or decreased ?
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Impact on cycle outcome
Bosch et al HR 2010
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ONGOING PREGNANCY RATE AND ONGOING IMPLANTATION
RATE ACROSS GROUPS OF PATIENTS WITH INCREASING LH
LEVELS ACCORDING TO PERCENTILE ANALYSIS
Groups of patients according to LH levels on day 8
Ongoing pregnancy rate
per oocyte retrieval
% (n)
Ongoing implantation
rate
% (n)
Pregnancy loss after hCG
detection before 12 weeks
% (n)
LH level on day 8
mean min max
0 - 25th 0.3 0.1 0.5 56.0 (14/25) 39.1 (18/46) 6.7 (1)
25 - 75th 1.0 0.6 1.9 40.3 (25/62) 24.6 (31/126) 7.4 (2)
75 - 100th 3.3 1.9 8.4 24.1 (7/29) 15.7 (8/51) 12.5 (1)
P < 0.010* P < 0.018* P < 0.71** Exact Chi-square for trend
Kolibianakis HR 2004
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Recombinant LH after antagonist initiation
Cedrin-Durnerin HR 2004
Pill pre-treatment/ 3 day interval, variable starting dose of rec FSH
Single dose antagonist administration by a follicle of 14-16mm
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Definition of OHSS
Iatrogenic complication (!) of
“controlled” (?) ovarian stimulation
Potentially fatal (!)
Risk factor (PCOS)
Triggering mechanism of hCG
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Intriguing
Iatrogenic Who is
responsible?
Ovarian stimulation How to stimulate?
HCG is the trigger HCG to be
replaced?
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Ovarian hyperstimulation syndromePubMed ( 01 09 2011)
o n : 2 275 citations
PubMed ( 30 01 2012)
o n : 2 333 citations
Pubmed (30 05 2012)
o n : 2 396 citations
Pubmed (17 03 2015)
o n: 2 837 citations
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Fatal OHSS
25 years old Japanese lady
Bilateral chest pain - dyspnoea
Pleural effusion
Fatal after respiratory insufficiency
Autopsy massive pulmonary edema
Semba Patol Int 2000
Fatal
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Maternal deathIn IVF in the Netherlands (1984 – 2008)
Death to OHSS : 3 / 100 000 IVF cycles
Respiratory distress (n : 2)
Cerebrovascular thrombosis (n : 1)
Braat HR 2010
Does it mean 30 / 1 000 000 ?
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Oocyte donors (GnRHa donors)
Triggering GnRHa hCG P
Subjects (n) 50 50
Age (y) 25 25
rFSH dose (U) 2 300 2 300
Eggs retrieved (mean)
17 19
OHSS rate 0 / 50 8 / 50 0.03
Melo RBMO 2009
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GnRH agonist triggering in GnRH antagonist cycles in OHSS risk
AIM avoiding OHSS Patients (n = 12) > 25 follicles GnRH agonist triggering and 1 500 hCG
35 hours later COC (n =20) Ongoing pregnancies 50 % (6/12) No OHSS
Humaidan RBMO 2009
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Oocyte banking (vitrification)
RCT P
Frozen Fresh
Ongoing pregnancy rate / ET
43.7 % 41.7 % NS
Clinical pregnancy rate / ET
55.0 % 56.0 % NS
Implantation rate 40.0 % 41.0 % NS
Similar results95 % CI : 0.7 – 1.3
Cobo HR 2010
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PubMed Search 18 02 2015
Keywords: corifollitropin alfa Publications : n=54
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Today’s treatment
GnRH antagonist
1 2 3 4 5 6 7 8 9 10
7-10 days FSHhCG
Corifollitropin alfarFSH
1 2 3 4 5 6 7 8 9 10
hCG
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Sustained follicle stimulants
A recombinant fusion molecule of FSH and the carboxy-terminal peptide (CTP) of the human chorionic gonadotropin-beta (hCG) subunit The first of a proposed new class of gonadotropins (Sustained Follicle Stimulants) with different pharmacokinetic properties but similar pharmacological features as wild-type FSH
Interacts only with the FSH receptor and not with the luteinizing hormone (LH) receptor
Fares et al Proc Natl Acad Sci USA 1992
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Duijkers et al. Hum Reprod. 2002 Devroey et al. J Clin Endocrinol Metab. 2004Fauser et al. Reprod Biomed Online 2010
Comparative pharmacokinetics
10987654321
Stimulation days
FSH
acti
vity
Therapeutic threshold
Corifollitropin alfarFSH
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Corifollitropin alfa
PlaceboCorifollitropin alfa
PlaceboCorifollitropin alfa
Engage and Ensure treatment regimen
GnRH antagonist (ganirelix 0.25 mg/d) day 5 through day of hCG
Stimulation day 5
hCG as soon as 3 follicles ≥17 mm
(or the day thereafter)
Stimulation day 8
Cycle day 2-3 =stimulation day 1
Daily rFSH(daily dose for 7 days)
Investigational group
Reference group
Placebo rFSH(daily dose for 7 days)
Placebo rFSH(daily dose for 7 days) Daily rFSH
Daily rFSH
IVF
or
ICSI
Lutealphase
support
Devroey et al. Hum Reprod 2009
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Prediction of OHSS with corifollitropin alfa versus rFSH
Patients at risk ≥ 18 or 19 follicles Sensitivity and specificity were 74.3% and
75.2% Preventive measure Switch from hCG to agonist triggering
Tarlatzis BC et Reprod Biomed Online 2012
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Risk of OHSS for corifollitropin alfa
OHSS Corifollitropin alfa recFSH
Patients(n) 71/1023 53/880
Mild (%) 3 3.5
Moderate (%) 2.2 1.3
Severe (%) 1.8 1.3
Tarlatzis BC et al Reprod Biomed Online 2012
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Does hCG administration on or before day 8 decrease the chance of
pregnancy?
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Day when hCG criterion were met
One-third of the patients, regardless of the corifollitropin alfa dose, met the criteria for hCG injection before or on stimulation day 8
0
10
20
30
40
5 6 7 8 9 1011 12 13 141516 1718
Day of hCG criteria
% o
f p
atie
nts
Corifollitropin alfa 100 µg
0
10
20
30
40
5 6 7 8 9 1011 1213141516 1718
Day of hCG criteria
% o
f p
atie
nts
Corifollitropin alfa 150 µg
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44,0
38,1
0
10
20
30
40
50
60
Pre
gn
ancy
Rat
e (%
)
248 485
Engage
150 microgram
≤ day 8
> day 844.0
38.1
Pregnancy rates for corifollitropin alfa group: Meeting criteria for hCG d8 vs. > d8
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Does delaying hCG administration by 1 day affect the chance of pregnancy?
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37,340,342
38,9
0
10
20
30
40
50
60
70
80
90
100
No
Yes
Pregnancy rates: hCG delay of 1 dayPr
egna
ncy
Rate
(%)
472 244 490 243N
Corifollitropin alfa Puregon
Engage
40.3 38.9 37.3 42
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Pregnancy Rates: Oocytes Retrieved
Engage
Fatemi HM et al Hum Reprod 2013
43,8
39,940,838,235,7
44,4
38,537,239,233,3
0
10
20
30
40
50
60
70 Corifollitropin alfa
Puregon
Preg
nanc
y Ra
te (%
)
84 16990 171 156N 136 178163188 133
1-5 6-9 10-13 14-18 >18Oocytes Retrieved
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Corifollitropin alfa on Day 2 versus Day 4
• Prospective randomized trial• Study population 52 patients• Total dose of rFSH significantly reduced
in CD4 (p=0.01)• Significant reduction of duration in CD4
Number of COS is comparable (12,8 versus 14,7)
• Ongoing pregnancy rates in CD2 group 48% versus 41% in CD4 group
Blockeel et al HR 2014
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(Cumulative) ongoing pregnancy rates &live birth rates in Engage trial
Corifollitropin alfa150 µgn = 756
Puregon®
200 IU/dayn = 750
Estimateddifferencea
(95% CI)
Ongoing PR per started cycle
per transfer
38.9%294/756
43.8%
38.1%286/750
40.6%
0.9% (–3.9 to 5.7)
3.1% (–2.0 to 8.2)
Live birth rates/ started cycle
35.6%275 in FU
34.4%266 in FU
Cumulative ongoing PR/ started cycle
47.2%148 ≥1 FTET
44.9%147 ≥1 FTET
Boostanfar et al. Hum Reprod 2010
aAdjusted for age and region. CI, confidence interval; FTET, frozen-thawed embryo transfer.
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Ongoing PR per started cycle
*More than 25% of patients had a value below the LLOQ and were all included in the <P25 group.
Doody KJ et al. Reprod Biomed Online 2011
Serum LH on Day 8 Engage
Treatment groupSerum LH level
IU/L
Ongoing pregnancy rateN n % 95% CI
Corifollitropin alfa P25≤0.62P50=0.96P75=1.58
<P25P25-P75
>P75
216*316176
7712568
35.639.6 38.6
[34.1; 45.2][29.3; 42.4][31.4; 46.3]
rFSHP25=0.91P50=1.57P75=2.66
<P25P25-P75
>P75
169340169
6012565
35.536.838.5
[28.3; 43.2][31.6; 42.1][31.1; 46.2]
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Cycles (n) 223
Mean age (year) 26.1 ± 4.2
OHSS risk 0
MII (mean +/-sd) 11 ± 9
Fertilization (%) 72
ET (mean) 1.8
PR/ET (%) 61
Miscarriage (%) 13
Implantation rate (%) 39
Elonva in egg donors with GnRH agonist triggering
Pellicer A et al personal communication 2013
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Requena et al. RBMOnline 2013
Evaluation of the degree of satisfaction (in egg donors)
Corifollitropin alfa(n=60)
recFSH(n=60)
Age (y) 23.2 24.4
Weight (kg) 65.6 64.9
Days of stim(n) 10 10
ready at D8 26% 27%
COC 15.1 16.5
MII 85% 77%
OHSS - -
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Evaluation of the degree of satisfaction (in egg donors)
Requena et al. RBMOnilne 2013
Corifollitropin(n=60)
recFSH(n=60)
satisfaction(10=completely satisfied)
9.1 9.3
pain(VAS 0-100)
13.5 12.9
preference(if previous cycle)
75% 25%
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Corifollitropin AlfaN = 424
rFSHN = 370
Gestational age, weeks 37.8 (3.2) 38.2 (2.8)
Female sex, n, mean (%) 210 (49.5%) 190 (51.4%)
Number of singletons 241 237
Weight at birth—singletons only, g 3297 (534) 3247 (586)
Weight at birth—all, g 2860 (755) 2928 (715)
Length at birth, cm 48.2 (4.1) 48.6 (4.1)
Head circumference, cm 33.6 (2.2) 33.5 (2.6)
Apgar score: 1 min 8.2 (1.5) 8.1 (1.5)
Apgar score: 5 min 9.1 (1.0) 9.1 (0.9)
Characteristics of live born infants
Care
Values are n, mean (SD) unless otherwise stated. Bonduelle M et al. Hum Reprod 2012
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Corifollitropin alfa in combination with GnRH agonist triggering (Pilot Study)
Corifollitropin alfa GnRH agonist triggering Egg retrieval After 1 hour 1500IU HCG After 7 days 1500IU HCG Micronized progesteron vaginally
Decleer et al. Facts Views Vision 2014
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Corifollitropin alfa in combination with GnRH agonist triggering (Pilot study)
Patients (n) 11
Age (y) 32
BMI (kg/m²) 24
COC (mean) 10
Pregnancies (n) 4
Decleer et al. Facts Views Vision 2014
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Addition of highly purified HMG after corifollitropin alfa in POR
• Stimulation protocol • Elonva + 300 IU Menopur • GnRH antagonist from day 7 of the cycle
Patients < 40 y Patients ≥ 40 y
Number 29 18
Pregnancy rate 8/29 (28%) 0/18 (0%)
Polyzos NP et al. Hum Reprod 2013
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Most Important Entry Criteria (PURSUE Study)
Inclusion criteria Indication for COS and IVF/ICSI Age ≥ 35 and ≤ 42 years Body weight ≥ 50 kg, and body mass index ≥ 18 and
≤ 32 kg/m2
Normal menstrual cycle (cycle length 24–35 days) Availability of ejaculatory sperm
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Number of Oocytes Retrieved
Corifollitropin Alfa 150 µg
rFSH300 IU/day
Estimated Difference
ANOVA (95% CI)
Per attempt
Mean (SD)
n = 694
10.7 (7.2)
n = 696
10.3 (6.8) 0.5 (–0.2 to 1.2)
Per oocyte pick-up
Mean (SD)
n = 675
11.0 (7.0)
n = 671
10.6 (6.7) 0.4 (–0.3 to 1.1)
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Primary End Point: Ongoing PR* %
of
pat
ien
ts
Pursue
ITT Group
23.9%26.9%
Boostanfar et al. ASRM 2012 San Diego
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Congenital malformations with corifollitropin alfa ( PURSUE study)
Corifollitropin alfa recFSH
Pregnancies (n) 154 167
Children(n) 183 196
Congenital malformations(n) 9 6
Congenital malformations (%) 4.9 3.1
Stegmann ASRM 2013 Boston
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Number of Subjects With OHSS (All Subjects Treated Group)
Corifollitropin Alfa 150 µgn = 692
rFSH 300 IU/day
n = 698
Incidence of OHSS, n (%)
Grade unknown 0 1 (0.1)
Grade I (mild) 7 (1.0) 1 (0.1)
Grade II (moderate) 5 (0.7) 4 (0.6)
Grade III (severe) 0 6 (0.9)
Total 12 (1.7) 12 (1.7)
OHSS reported as SAE 0 5 (0.7)
Hospitalization 0 2 (0.3)
Grade II and/or III 5 (0.7) 10 (1.4)
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Coda
Yesterday Nowadays Pro
• GnRH agonist long protocol
• Daily rFSH injections
• hCG for final egg maturation
• Patient unfriendly
• OHSS ± 5%
• GnRH antagonist
• Corifollitropin alfa
• GnRH agonist for final egg maturation if needed
• Patient friendly
• OHSS ≈ 0%
• OHSS Free Clinic
• Safe and simple
• Safe and simple
• Safe
• Safe
Acknowledgements to Helena Deryckere